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Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date.

Tuttolomondo A, Pecoraro R, Pinto A - Drug Des Devel Ther (2014)

Bottom Line: TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect.Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage.On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Department of Internal and Specialistic Medicine, University of Palermo, Palermo, Italy.

ABSTRACT
The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuroinflammatory cascade has been reported to be activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory reaction is tumor necrosis factor (TNF)-α, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF-α has been shown to have an important role within the central nervous system; its properties include activation of microglia and astrocytes, influence on blood-brain barrier permeability, and influences on glutamatergic transmission and synaptic plasticity. TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF-α activity during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In some studies using animal models, researchers have reported a limitation of TBI-induced cerebral ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.

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TNF-α-related crucial events within the CNS during TBI and acute ischemic stroke.Abbreviations: Akt, serine/threonine-protein kinases; AP2, activating protein 2; APC, antigen presenting cell; Cabp, calcium binding protein; CaM, calmodulin; CNS, central nervous system; eNOS, endothelial nitric oxide synthase; EPCR, endothelial protein C receptor; GLT-1, glial glutamate transporter; hsp90, heat shock protein 90; Ig, immunoglobulin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; ONS, base-modified oligonucleotides; PAI, plasminogen-activating inhibitor; PAL-1, phenylalanine ammonia-lyase I; PKA, protein kinase A; SOD, superoxide dismutase; TBI, traumatic brain injury; TF, tissue factor; t-PA, tissue plasminogen activator; TNF, tumor necrosis factor; u-PA, urokinase plasminogen activator; VWF, von Willebrand factor; VIIIa, factor VIIIa; Va, factor Va.
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f2-dddt-8-2221: TNF-α-related crucial events within the CNS during TBI and acute ischemic stroke.Abbreviations: Akt, serine/threonine-protein kinases; AP2, activating protein 2; APC, antigen presenting cell; Cabp, calcium binding protein; CaM, calmodulin; CNS, central nervous system; eNOS, endothelial nitric oxide synthase; EPCR, endothelial protein C receptor; GLT-1, glial glutamate transporter; hsp90, heat shock protein 90; Ig, immunoglobulin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; ONS, base-modified oligonucleotides; PAI, plasminogen-activating inhibitor; PAL-1, phenylalanine ammonia-lyase I; PKA, protein kinase A; SOD, superoxide dismutase; TBI, traumatic brain injury; TF, tissue factor; t-PA, tissue plasminogen activator; TNF, tumor necrosis factor; u-PA, urokinase plasminogen activator; VWF, von Willebrand factor; VIIIa, factor VIIIa; Va, factor Va.

Mentions: Several reports show that TNF-α is involved in several crucial pathways within the CNS (Figure 2).40–47 These pathways induce the activation of microglia and astrocytes, act on BBB integrity, enhance glutamatergic transmission, and regulate synaptic plasticity. Furthermore, a mechanism of scaling of excitatory synapses has been reported as linked to TNF-α promotion of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and downregulation of γ-aminobutyric acid (GABA) receptors on the cell surface. These findings could suggest a possible role of TNF-α in the regulation of synaptic transmission at excitatory synapses, thus enhancing excitatory synaptic transmission and lowering inhibitory synaptic transmission.48–51


Studies of selective TNF inhibitors in the treatment of brain injury from stroke and trauma: a review of the evidence to date.

Tuttolomondo A, Pecoraro R, Pinto A - Drug Des Devel Ther (2014)

TNF-α-related crucial events within the CNS during TBI and acute ischemic stroke.Abbreviations: Akt, serine/threonine-protein kinases; AP2, activating protein 2; APC, antigen presenting cell; Cabp, calcium binding protein; CaM, calmodulin; CNS, central nervous system; eNOS, endothelial nitric oxide synthase; EPCR, endothelial protein C receptor; GLT-1, glial glutamate transporter; hsp90, heat shock protein 90; Ig, immunoglobulin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; ONS, base-modified oligonucleotides; PAI, plasminogen-activating inhibitor; PAL-1, phenylalanine ammonia-lyase I; PKA, protein kinase A; SOD, superoxide dismutase; TBI, traumatic brain injury; TF, tissue factor; t-PA, tissue plasminogen activator; TNF, tumor necrosis factor; u-PA, urokinase plasminogen activator; VWF, von Willebrand factor; VIIIa, factor VIIIa; Va, factor Va.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232043&req=5

f2-dddt-8-2221: TNF-α-related crucial events within the CNS during TBI and acute ischemic stroke.Abbreviations: Akt, serine/threonine-protein kinases; AP2, activating protein 2; APC, antigen presenting cell; Cabp, calcium binding protein; CaM, calmodulin; CNS, central nervous system; eNOS, endothelial nitric oxide synthase; EPCR, endothelial protein C receptor; GLT-1, glial glutamate transporter; hsp90, heat shock protein 90; Ig, immunoglobulin; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; ONS, base-modified oligonucleotides; PAI, plasminogen-activating inhibitor; PAL-1, phenylalanine ammonia-lyase I; PKA, protein kinase A; SOD, superoxide dismutase; TBI, traumatic brain injury; TF, tissue factor; t-PA, tissue plasminogen activator; TNF, tumor necrosis factor; u-PA, urokinase plasminogen activator; VWF, von Willebrand factor; VIIIa, factor VIIIa; Va, factor Va.
Mentions: Several reports show that TNF-α is involved in several crucial pathways within the CNS (Figure 2).40–47 These pathways induce the activation of microglia and astrocytes, act on BBB integrity, enhance glutamatergic transmission, and regulate synaptic plasticity. Furthermore, a mechanism of scaling of excitatory synapses has been reported as linked to TNF-α promotion of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and downregulation of γ-aminobutyric acid (GABA) receptors on the cell surface. These findings could suggest a possible role of TNF-α in the regulation of synaptic transmission at excitatory synapses, thus enhancing excitatory synaptic transmission and lowering inhibitory synaptic transmission.48–51

Bottom Line: TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect.Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage.On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Department of Internal and Specialistic Medicine, University of Palermo, Palermo, Italy.

ABSTRACT
The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuroinflammatory cascade has been reported to be activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory reaction is tumor necrosis factor (TNF)-α, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF-α has been shown to have an important role within the central nervous system; its properties include activation of microglia and astrocytes, influence on blood-brain barrier permeability, and influences on glutamatergic transmission and synaptic plasticity. TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF-α activity during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In some studies using animal models, researchers have reported a limitation of TBI-induced cerebral ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.

Show MeSH
Related in: MedlinePlus